Beyond cells: The extracellular circulating 20S proteasomes

Dwivedi, Vandita; Yaniv, Karina; Sharon, Michal

doi:10.1016/j.bbadis.2020.166041

Cited by 27 publications

(24 citation statements)

References 120 publications

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“…Elevated 20S proteasome was found in several other pathological conditions such as carcinoma [47], burn injuries [48] and autoimmune diseases [49]. These observations confirm our findings that patients in our study cohort with elevated 20S proteasome levels suffer from severe tissue damage and hyper-activated immune system, whereas these factors together lead to increased apoptosis and thus probably higher risk of invasive ventilation or higher in-hospital mortality [50].…”

Section: S Proteasomesupporting

confidence: 89%

Clinical Relevance of Elevated Soluble ST2, HSP27 and 20S Proteasome in Patients with COVID-19

Wendt¹,

Lingitz²,

Laggner³

et al. 2021

Preprint

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Although, severe acute respiratory syndrome coronavirus – 2 (SARS-CoV 2) represents one of the biggest challenges in the world today, the exact immunopathogenic mechanism that leads to severe or critical Coronavirus Disease 2019 (COVID-19) has remained incompletely understood. Several studies have indicated that high systemic plasma levels of inflammatory cytokines result in the so-called “cytokine storm”, with subsequent development of microthrombosis, disseminated intravascular coagulation, and multiorgan-failure. Therefore, we reasoned that elevated inflammatory cytokine might act as prognostic factors. Here, we analyzed 245 serum samples of patients with COVID-19, collected at hospital admission. We assessed the levels of heat shock protein 27 (HSP27), soluble suppressor of tumorigenicity- 2 (sST2), caspase cleaved cytokeratin 18 (cCK18), 20S proteasome, and tumor necrosis factor receptor 1 (TNFR-1) and explored their associations with overall-, 30-, 60-, 90-day- and in-hospital mortality. Moreover, we investigated their association with the risk of ventilation. We demonstrated that increased serum sST2 was uni- and multivariably associated with all endpoints. However, we also identified 20S proteasome as independent prognostic factor for in-hospital mortality. Furthermore, elevated HSP27, sST2, and 20S proteasome levels at hospital admission were univariably associated with higher risk of invasive ventilation. These findings could help to identify high-risk patients early in the course of COVID-19.

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Section: S Proteasomesupporting

confidence: 89%

Clinical Relevance of Elevated Soluble ST2, HSP27 and 20S Proteasome in Patients with COVID-19

Wendt¹,

Lingitz²,

Laggner³

et al. 2021

Preprint

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“…Lastly, numerous clinical studies show that, 20S proteasome complexes circulate freely in blood plasma (Dwivedi et al, 2021). This observation raises the possibility that they may also be secreted by an additional yet unknown mechanism, which is not involving EVs, underscoring further need to investigate circulating 20S proteasomes in the context of parasitic infection.…”

mentioning

confidence: 99%

Cell communication and protein degradation: All in one parasitic package

Sharon

Regev‐Rudzki

2021

J of Extracellular Vesicle

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A parasite is a unicellular or multicellular organism that is dependent on another organism (host) for its survival and proliferation. The parasite benefits from a prolonged association with its host (Loker & Hofkin, 2015), as without it, the parasite cannot grow and multiply. Thus, parasites must keep their host alive for as long as possible without killing it, yet their infection may cause diseases and, in some cases, like malaria, even mortality.Three main classes of parasites can cause disease in humans: protozoa, helminths and ectoparasites. The former are unicellular eukaryotic parasites (e.g., Plasmodium falciparum and Trypanosoma brucei), whereas the helminths are parasitic worms (e.g., Schistosoma haematobium and Fasciola hepatica), and the ectoparasites, organisms that infest the host skin (e.g., Haemaphysalis longicornis and Sarcoptes scabiei). These classes of parasites are master manipulators whose life cycles feature unique adaptions, involving sophisticated strategies to alter the host environment, including the secretion of multipurpose extracellular vesicles (EVs) (Coakley et al., 2015;Ofir-Birin & Regev-Rudzki, 2019).EVs are heterogeneous in terms of size (30-500 nm in diameter) and transfer functional signals to target cells by carrying a cornucopia of different molecules, such as proteins, glycans, lipids, RNA and DNA (Schorey et al., 2015;Tkach & Théry, 2016). Since the release of EVs is an integral part of a parasite's life cycle and course of the infection, it stands to reason that these organelles are essential for their survival. Indeed, these shuttling vesicles provide a robust delivery system to facilitate parasitic growth and development, the transfer of virulence factors, adherence to host tissues, and evasion of immune responses (Mardahl et al., 2019;Ofir-Birin et al., 2017). They effectively manipulate the host's immune system by inhibiting or activating responses as well as by affecting a variety of other (non-immune) target human cells (

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“…Our insight into how extracellular proteostasis operates and functions remains unclear, although more than 10% of the protein-encoding gene products are secreted 28 and the majority of proteopathies, a group of human diseases associated with toxic protein accumulation and aggregation, occur in extracellular fluids 29 . Since the discovery of circulating proteasomes (hereafter referred to as c-proteasomes) in human blood ~30 years ago 30 , the clinical relevance of these components has been examined in various diseases, including myeloid and lymphoid malignancies, solid tumors, autoimmune disorders, sepsis, mild cognitive impairment, and other clinical conditions 31 , 32 . However, many of these studies used limited cohort sizes without further validation with independent reproduction.…”

Section: Circulating Proteasomesmentioning

confidence: 99%

“…Here, we summarize the findings of previous studies on c-proteasomes (principally in chronological order) and discuss some of the key technical aspects of c-proteasome research. The availability of related reviews precludes the discussion on the extracellular proteasomes found in alveolar, cerebrospinal, and epididymal fluids, as well as other extracellular spaces 31 , 33 .…”

Section: Circulating Proteasomesmentioning

confidence: 99%

Concept and application of circulating proteasomes

et al. 2021

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Proteostasis is primarily a function of protein synthesis and degradation. Although the components and processes involved in intracellular proteostasis have been studied extensively, it is apparent that extracellular proteostasis is equitably crucial for the viability of organisms. The 26S proteasome, a unique ATP-dependent proteolytic complex in eukaryotic cells, contributes to the majority of intracellular proteolysis. Accumulating evidence suggests the presence of intact 20S proteasomes in the circulatory system (c-proteasomes), and similar to other plasma proteins, the levels of these c-proteasomes may vary, potentially reflecting specific pathophysiological conditions. Under normal conditions, the concentration of c-proteasomes has been reported to be in the range of ~0.2–2 μg/mL, which is ~2–4-fold lower than that of functional plasma proteins but markedly higher than that of signaling proteins. The characterization of c-proteasomes, such as their origin, structure, role, and clearance, has been delayed mainly due to technical limitations. In this review, we summarize the current perspectives pertaining to c-proteasomes, focusing on the methodology, including our experimental understanding. We believe that once the pathological relevance of c-proteasomes is revealed, these unique components may be utilized in the diagnosis and prognosis of diverse human diseases.

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Beyond cells: The extracellular circulating 20S proteasomes

Cited by 27 publications

References 120 publications

Clinical Relevance of Elevated Soluble ST2, HSP27 and 20S Proteasome in Patients with COVID-19

Clinical Relevance of Elevated Soluble ST2, HSP27 and 20S Proteasome in Patients with COVID-19

Cell communication and protein degradation: All in one parasitic package

Concept and application of circulating proteasomes

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